diagnostics Review Renal Complications Related to Checkpoint Inhibitors: Diagnostic and Therapeutic Strategies Julie Belliere 1,2,3,*, Julien Mazieres 3,4,5, Nicolas Meyer 3,4,6, Leila Chebane 7 and Fabien Despas 7,8 1 Department of Nephrology and Organ Transplantation, University Hospital of Toulouse, 31 400 Toulouse, France 2 INSERM U1048, Institute of Metabolic and Cardiovascular Diseases, 31 400 Toulouse, France 3 Department of Biological Sciences, Paul Sabatier University, 31 400 Toulouse, France; [email protected] (J.M.); [email protected] (N.M.) 4 Institut Universitaire du Cancer Toulouse Oncopole, 31 400 Toulouse, France 5 Department of Pneumology, University Hospital of Toulouse, 31 400 Toulouse, France 6 Department of Dermatology, University Hospital of Toulouse, 31 400 Toulouse, France 7 Service Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, 31 400 Toulouse, France; [email protected] (L.C.); [email protected] (F.D.) 8 Service de Pharmacologie Médicale et Clinique, Faculté de Médecine, Université Paul Sabatier, Equipe PEPSS Centre d’Investigation Clinique 1436, INSERM 1297, 31 400 Toulouse, France * Correspondence: [email protected] Abstract: Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have unprecedentedly improved global prognosis in several types of cancers. However, they are asso- Citation: Belliere, J.; Mazieres, J.; ciated with the occurrence of immune-related adverse events. Despite their low incidence, renal Meyer, N.; Chebane, L.; Despas, F. complications can interfere with the oncologic strategy. The breaking of peripheral tolerance and the Renal Complications Related to emergence of auto- or drug-reactive T-cells are the main pathophysiological hypotheses to explain Checkpoint Inhibitors: Diagnostic renal complications after ICI exposure. ICIs can induce a large spectrum of renal symptoms with and Therapeutic Strategies. variable severity (from isolated electrolyte disorders to dialysis-dependent acute kidney injury (AKI)) Diagnostics 2021, 11, 1187. https:// and presentation (acute tubule-interstitial nephritis in >90% of cases and a minority of glomerular doi.org/10.3390/diagnostics11071187 diseases). In this review, the current trends in diagnosis and treatment strategies are summarized. The Academic Editors: Dil Sahali, diagnosis of ICI-related renal complications requires special steps to avoid confounding factors, iden- Hassan Izzedine, Vincent Audard, tify known risk factors (lower baseline estimated glomerular filtration rate, proton pump inhibitor Carole Henique, Mario Ollero and use, and combination ICI therapy), and prove ICI causality, even after long-term exposure (weeks Henning Reis to months). A kidney biopsy should be performed as soon as possible. The treatment strategies rely on ICI discontinuation as well as co-medications, corticosteroids for 2 months, and tailored Received: 28 February 2021 immunosuppressive drugs when renal response is not achieved. Accepted: 28 June 2021 Published: 30 June 2021 Keywords: renal complications; acute kidney injury; immune check point inhibitors; immune-related adverse events Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Immune checkpoint inhibitors (ICIs) have been approved in the field of oncology, providing an original antitumor approach compared to chemotherapies. Their utilization relies on the drug’s capacity to repair dysfunctional T cells resulting in the regression of Copyright: © 2021 by the authors. various cancers. The “price to pay” is the risk of autoimmunity, leading to immune-related Licensee MDPI, Basel, Switzerland. adverse events (irAEs) and, in some cases, end organ damage. The contributions of ICIs This article is an open access article to kidney toxicity have been neglected and underestimated for several years, but it has distributed under the terms and now been acknowledged that they lead to acute kidney injury (AKI). This impacts renal conditions of the Creative Commons function and, subsequently, oncologic treatment choices must be weighed. This review Attribution (CC BY) license (https:// focuses on diagnostic and therapeutic strategies for ICI-related renal complications. creativecommons.org/licenses/by/ 4.0/). Diagnostics 2021, 11, 1187. https://doi.org/10.3390/diagnostics11071187 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 1187 2 of 15 1.1. ICIs Both cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) play a role as physiologic brakes on unrestrained cytotoxic T-effector function. CTLA-4 (CD 152) is a member of the B7/CD28 family. It mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. The CTLA4 blockade also restores T cell three-signal activation. Ipilimumab is the first and only FDA- approved CTLA-4 inhibitor. PD-1 is an inhibitory transmembrane protein expressed in T cells, B cells, natural killer cells, and myeloid-derived suppressor cells. Programmed death- ligand 1 (PD-L1) is expressed on the surface of multiple tissue types, including many tumor cells and hematopoietic cells. PD-L2 is more restricted to hematopoietic cells. A blockade of the PD-1/PDL-1 pathway can enhance antitumor T cell reactivity and promote immune control over cancerous cells. Since the FDA approval of ipilimumab (human IgG1 k anti- CTLA-4 monoclonal antibody) in 2011, eight more ICIs have been approved for cancer therapy. PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab) and PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab) are on the current list of approved agents [1]. Recent anti-CTLA4 antibodies such as tremelimumab and quavonlimab (MK-1308) are now used in combination with anti-PDL1. For example, a combination of the anti-CTLA4 tremelimumab and the anti-PDL1 durvalumab is promising in advanced non-small cell lung cancer [2], head and neck squamous cell carcinoma [3], and other solid tumors such as advanced hepatocellular carcinoma [4]. The use of quavonlimab in combination with pembrolizumab in first-line treatment has also been reported in advanced non-small-cell lung cancer [5] and advanced small-cell lung cancer [6]. Recent studies have identified several new immune checkpoint targets, such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), and V-domain Ig suppressor of T cell activation (VISTA) [7]. The studies have generated promising results in clinical trials. As reported in Table1, the number of ICIs is increasing. Table 1. ICI list with indications. ICI Class Molecule Date of Approval Type of Indications melanoma, renal cell carcinoma, CRC Ipilimumab 2011 mesothelioma, in combination with durvalumab in advanced anti-CTLA4 Tremelimumab 2015 non-small cell lung cancer, head and neck squamous cell Quavonlimab current folder carcinoma, advanced hepatocellular carcinoma melanoma, hepatocellular carcinoma, cervical cancer, advanced NSCLC, gastric cancers, Hodgkin lymphoma, primary Pembrolizumab 2014 mediastinal large B-cell lymphoma, urothelial cancer, cutaneous anti-PD1 Nivolumab 2014 squamous cell carcinoma cemiplimab 2018 melanoma, head and neck, hepatocellular carcinoma, renal cell carcinoma, CRC, small lung cancer, advanced NSCLC cutaneous squamous cell carcinoma advanced small cell lung cancer, advanced NSCLC, triple Atezolizumab 2016 negative breast cancer, urothelial cancer anti-PDL1 Avelumab 2017 Merkel cell carcinoma, urothelial cancer Durvalumab 2017 urothelial cancer, locally advanced NSCLC, advanced SCLC metastatic RCC, metastatic breast cancer, melanoma, advanced Eftilagimod alpha FDA approval March 2020 anti-LAG3 NSCLC and head and neck squamous cell carcinoma Relatlimab current folder clinical trials recruiting TSR-022 MBG453 Sym023 INCAGN2390 anti-TIM3 current folder clinical trials recruiting LY3321367 BMS-9862 SHR-170258 RO7121661 Diagnostics 2021, 11, 1187 3 of 15 Table 1. Cont. ICI Class Molecule Date of Approval Type of Indications Tiragolumab MK-7684 Etigilimab FDA approval January 2021 PD-L1-high non-small cell lung cancer anti-TIGIT BMS-986207 current folder clinical trials recruiting AB-154 ASP-8374 JNJ-61610588 anti-VISTA current folder clinical trials recruiting CA-170 anti-B7-H3 Enoblituzumab FDA approval December 2020 Patients with Pretreated Metastatic HER2-Positive Breast Cancer CRC: colorectal cancer; NSCLC: Non-small-cell lung carcinoma; SCLC: Small-cell lung carcinoma. While therapy with this class of agents has resulted in improved clinical outcomes for patients with multiple tumor types, a broad spectrum of irAEs may affect any organ system, with variable clinical presentations. 1.2. Incidence of Renal irAEs Although severe irAEs remain rare (~10% of the cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately [8]. The highest frequency has been observed with CTLA4 antibodies and combinations of ICIs. Global grade III and IV toxicities occur in 20% of patients. Renal toxicities are not the most frequent [9]: the incidence of AKI is 2% for ipilimumab, 1.9% for nivolumab, 1.4% for pembrolizumab, and 4.9% for the ipilimumab and nivolumab combination [10], but it is hypothesized that it will rise to between 9.9 and 29% in the near future [11]. The proportion of renal irAEs has not yet